WO2007090134A2

WO2007090134A2 - Use of vanilloid receptor-1 antagonists for the prevention and treatment of glaucoma

Info

Publication number: WO2007090134A2
Application number: PCT/US2007/061331
Authority: WO
Inventors: Martin B. Wax; Iok-Hou Pang; Allan Shepard
Original assignee: Alcon Manufacturing Ltd
Current assignee: Alcon Research LLC
Priority date: 2006-01-31
Filing date: 2007-01-31
Publication date: 2007-08-09
Anticipated expiration: 2008-07-31
Also published as: TW200738232A; AR059244A1; WO2007090134A3; UY30120A1

Abstract

Compositions and methods for treating glaucoma and for treating or preventing retina damage resulting from glaucoma with vanilloid receptor-1 antagonist compounds are disclosed.

Description

USE OF VANILLOID RECEPTOR-1 ANTAGONISTS FOR THE PREVENTION AND TREATMENT OF GLAUCOMA

This application claims priority to U.S. Provisional application number 60/763,740, filed January 31 , 2006.

The present invention is directed to compounds which function as vaπilloid receptor-1 (VR-1 ) antagonists for treating persons suffering from acute or chronic degenerative conditions or diseases of the eye.

Background of the Invention

The vanilloid receptor-1 (VR-1 , also named TRPV1 or capsaicin receptor) belongs to the transient receptor potential (TRP) family of cation channels. Recent findings show that the VR-1 is associated with several other proteins and these proteins together form a molecular complex, collectively called "transducisome." These other proteins include scaffolding proteins, neurotrophic factor receptors, especially Trk A and Trk B, phospholipase C, and protein kinase C (Nagy et al., Eur. J. Pharmacol. 500:351-369 (2004)).

VR-1 is activated by physical changes of the environment, notably noxious heat. Recently, this receptor has also been found in nerve fibers that innervate Meissner corpuscules (Pare et al., J. Neurosci. 21 :7236-7246 (2001 )), suggesting that VR-1 may be involved in the detection of mechanical deformation, such as that induced by pressure. Activation of the receptor evokes an inward current, predominantly calcium current, across the cell membrane. The VR-1 -mediated current can be enhanced by membrane depolarization (Ahern & Premkumar, J. Physiol. 545:441-451 (2002)). In addition to physical changes, the receptor can be activated by many endogenous molecules, such as ATP, anandamide, N- arachidonoyl-dopamine, N-oleoyldopamine, lipoxygenase products (including 12- (S)-HPETE, 15-(S)-HPETE, 5-(S)-HETE, and 15-(S)-HETE). Certain specific exogenous chemicals, such as capsaicin, resin iferatoxin, and ethanol, can bind to the VR-1 receptor and activate it. Some other agents, such as glutamate and ATP, can activate their own receptor and increase the activity of the VR-1 receptor via posttranslational modifications (Nagy etal. 2004). Glaucoma is a family of diseases, each of which is distinguished by a particular characteristic of that disease form. Primary open angle glaucoma (POAG) is characterized by typical glaucomatous changes to optic nerve head topography, arcurate scotomas in the visual field, an open angle, and is usually associated with elevated intraocular pressure (lOP). Normotensive glaucoma (NTG) or low tension glaucoma is very similar to POAG except the IOP for these patients is in the normal range relative to the general population. Other forms of glaucoma include closed angle glaucoma and pigmentary dispersion glaucoma. All these forms of glaucoma are similar in that patients suffer from the progressive loss of retinal ganglion cells (RGC) due to apoptotic death, which leads to a reduction of visual field and the eventual loss of vision. Current therapies for the treatment of glaucoma, in particular POAG and NTG, strive to slow the progression of the visual field loss by lowering and controlling IOP. This is done by either IOP lowering drugs or argon laser trabeculoplasty and/or by glaucoma filtration surgery. Long-term studies show that lowering IOP (even in NTG patients) is effective in slowing the disease progression in many patients. Unfortunately, there are patients who continue to lose visual field despite having their IOP lowered.

The essential molecular mechanism involved in RGC death secondary to glaucoma has not been unequivocally determined. However, excessive glύtamate in the retina causing excitotoxicity to RGC and retinal vascular abnormalities leading to ischemic episodes of the RGC has been proposed to contribute to the pathology of this disease.

Current approved glaucoma therapies seek only to lower IOP without directly addressing the retinal damage associated with glaucoma. What is needed is an ocular therapy targeted to protect or rescue RGC from the glaucomatous damage.

Summary of the Invention

The present invention overcomes these and other drawbacks of the prior art by providing compounds and/or compositions which interfere with the pathogenic process that causes retinal damage in glaucoma. More specifically, the present invention is directed to the use of compounds that inhibit the activation of vanilloid receptor-1 (VR-1 ) suffering from glaucoma and glaucomatous retinopathy.

Brief Description of the Drawings

The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present invention. The invention may be better understood by reference to these drawings in combination with the detailed description of specific embodiments presented herein.

FIG. 1 shows the cytotoxic effect of VR-1 agonist resiniferatoxin on cultured rat RGC. Asterisks represent statistical significance (p < 0.05) when compared to the vehicle control group by one-way ANOVA then Dunnett's test.

FIG. 2 shows the dose-dependent effect of capsaicin isomers (VR-1 agonists) on RGC survival. Asterisks represent statistical significance (p < 0.05) when compared to the control group by one-way ANOVA then Dunnett's test.

FIG. 3 shows the protective effect of VR-1 antagonist 6-iododihydrocapsaicin against resiniferatoxin-induced death of cultured rat RGC. Asterisks represent statistical significance (p < 0.05) when compared to the vehicle control group by one-way ANOVA then Dunnett's test. Rftx = resiniferatoxin.

FIG. 4 shows the effect of protective effect of VR-1 antagonist 6- iododihydrocapsaicin (l-DiH-Cap) on VR-1 agonist-induced RGC toxicity. Asterisks represent statistical significance (p < 0.05) when compared to the control group by one-way ANOVA then Dunnett's test. Rftx = resiniferatoxin; Z- Cap = Z-capsaicin; E-Cap = E-capsaicin.

Description of Preferred Embodiments

Glaucoma is characterized by a progressive optic neuropathy and retinopathy that lead to the eventual apoptotic death of retinal ganglion cells (RCG) and thus loss of vision. A major risk factor of glaucoma is ocular hypertension. At this time, it is not known how the excessive increase in intraocular pressure (lOP) leads to the death of RGC. The present inventors discovered that compounds, such as resiniferatoxin and isomers of capsaicin, that activate the VR- 1 receptor can and 2; FIG. 1 and FIG. 2). They further demonstrated that a VR-1 antagonist, 6- iododihydrocapsaicin, can antagonize this toxic effect (Example 3; FIG. 3 and FIG. 4). The results support that VR-1 receptor contributes to the pathology of

5 glaucomatous retinopathy. Specifically, it is believed that the potential involvement of VR-1 in the detection of mechanical deformation suggests that it can also function as a pressure-sensor in the RGC. An abnormally high intraocular pressure can activate the VR-1 , which induces an excessive influx of calcium and causes apoptotic death of the RGC. In addition, in glaucoma, o vascular insufficiency has been proposed as one of the contributing mechanisms. Under these conditions, the RGC will experience episodes of ischemia or hypoperfusion. Ischemia leads to membrane depolarization in neuronal cells, which sensitizes the VR-1 and enhances its responsiveness to physical changes of the environment. Furthermore, increase of glutamate in the vitreous of s glaucoma patients has been reported. Glutamate can increase the activity of the VR-1 receptor. Thus, the potential contributions of elevated lOP, ischemia and glutamate to the disease process in glaucoma and their augmentation of VR-1 activity are consistent with the theory of the invention.

Q The present invention, therefore, provides methods for the prevention and/or treatment of glaucoma by administering a composition containing at least one VR-1 antagonist or a derivative thereof. The present invention further provides a method for preventing damage to retinal ganglion cells resulting from glaucoma by administering a composition containing at least one VR-1 antagonist 5 or a derivative thereof.

While it is contemplated that virtually any VR-1 antagonist will be useful in the compositions and methods of the present invention, preferred VR-1 antagonists include capsazepine; 6-iodono/τiihydrocapsaicin; 2-substituted 0 pyrrolidinethiourea derivatives 4a and 4b disclosed in Park et a/., Bioorg Med Chem Lett., 13:197-200 (2003); N, N', N"-trisubstituted thiourea derivatives 8k, 8I, 8n, 8x, 8y, 8z, 8a' disclosed in Park et ai, Bioorg. Med. Chem. Lett., 13: 601 -604 (2003); 4-(2-pyridyl)piperazine-1-carboxamide derivatives 1-3, 5-8, 10-16 18-25, 28, 30, 31 disclosed in Sun et ai, Bioorg. Med. Chem. Lett., 13: 3611 -3616 5 (2003); 19N-[4-methylsulfonylamino)benzyl] thiourea derivatives 2, 6, 7, 8, 10, 1 1 , 25, 29, 34, 46, 47, 48, and 49 disclosed in Lee et ai, Bioorg. Med. Chem., 12:371- 385 (2004); 7-hydroxynaphthalen-1-yl-urea and -amide derivatives 4, 5a, 5e, 5f, 5h, 5k, 5n, 6k, 6o, 6p, and 6q

Lett. 14:531-534 (2004); N-4-substituted-benzyl-n'-tert-butylbenzyl thiourea derivatives 6c, 6f, 6j, 7b, 7c, 7ά, 7e, 7f, 7g, 7j, 7k, 7I, 7m, and 7n disclosed in Park et al., Bioorg. Med. Chem. _. Lett. 14:787-791 (2004); N-4- s methansulfonamidobenzyl-N'-2-substituted-4-tert-butyl-benzyl thiourea derivatives 2, 5a-5n, 6d, 6h, and 6n disclosed in Park et al., Bioorg. Med. Chem. Lett. 14:1693-1696 (2004); N-(3-acyloxy-2-benzylpropyl)-N'-[4-(methylsulfonylamino)- benzyl]thiourea derivatives 1 , 2, 3, 12, 13, 14, 17, 25, 28, 33, 41 , 42, 43, and 45 disclosed in Lee et al., Bioorg. Med. Chem. Lett., 14:2291-2297 (2004); Urea io analogs 1-20 disclosed in Rami et al., Bioorg. Med. Chem. Lett., 14: 3631-3634 (2004); pyridazinylpiperazine deriviatives 14, 15, 22, 24, 26, 28 disclosed in Tafesse et al., Bioorg. Med. Chem. Lett., 14: 5513-5519 (2004); chain-branched 1 ,3-dibenzylthiourea derivatives 6, 7, 8, 9, 10, 11 , 17, 18, 19, 21 , 26, 27, 28, 29, 30, 37 disclosed in Ryu et al., Bioorg. Med. Chem. Lett. 14:1751-1755 (2004); N- i5 isoquinolin-5-yl-N'-aralkyl-urea and -amide derivatives disclosed in Jetter et al., Bioorg. Med. Chem. Lett. 14:3053-3056 (2004); N-(4-chlorobenzyl)-N'-(4-hydroxy- 3-iodo-5-methoxybenzyl)thiourea disclosed in Toth et al., MoI. Pharmacol. 65:282- 291 (2004); 5-iodo-phenylacetylrinvanil and 6-iodo-phenylacetylrinvanil disclosed in Appendino et al., J. Pharmacol. Exp. Ther. 312:561-570 (2005); N-aryl

20 cinnamide derivatives 1 , 39, 45a, 45b-45f, 46a-46p, 47a, 47b, 47d, 48b-48f, 48h- 48n, 48p, 48q, 48s-48x, 49a, and 49b disclosed in Doherty et al., J. Med. Chem. 48:71 -90 (2005); pyridinylpiperazine urea derivatives 4, 14, 15, 16, 20, 24, 28, 34, 35, 36, 40, 41 disclosed in Swanson et al., J. Med. Chem., 48: 1857-1872 (2005); and thiazole carboxamide derivatives 1 , 4a, 4f, 4g, 4h, 4i, 4j, 25b, 25c, 25i, 28d,

25 28 disclosed in Xi et al., Bioorg. Med. Chem. Lett. 15:5211-5217 (2005).

In general, the Compounds of this invention may be administered orally with daily dosage of these Compounds ranging between about 0.001 and about 500 milligrams. The preferred total daily dose ranges between about 1 and about so 100 milligrams. Non-oral administration, such as, intravitreal, topical ocular, transdermal patch, subdermal, parenteral, intraocular, subconjunctival, or retrobulbar or subtenon's injection, trans scleral (including iontophoresis), or slow release biodegradable polymers or liposomes may require an adjustment of the total daily dose necessary to provide a therapeutically effective amount of the

35 compound. The Compounds can also be delivered in ocular irrigating solutions. Concentrations should range from about 0.001 μM to about 100 μM, preferably about 0.01 μM to about 10 μM. As stated above, the Compounds can be incorporated into various types of ophthalmic formulations for delivery to the eye (e.g., topically, intracamerally, intravitreal, or via an implant). They may be combined with ophthalmologically acceptable preservatives, surfactants, viscosity enhancers, gelling agents, penetration enhancers, buffers, sodium chloride, and water to form aqueous, sterile ophthalmic suspensions or solutions or preformed gels or gels formed in situ. Ophthalmic solution formulations may be prepared by dissolving the compound in a physiologically acceptable isotonic aqueous buffer. Further, the ophthalmic solution may include an ophthalmologically acceptable surfactant to assist in dissolving the compound. The ophthalmic solutions may contain a viscosity enhancer, such as, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone, or the like, to improve the retention of the formulation in the conjunctival sac. In order to prepare sterile ophthalmic ointment formulations, the active ingredient is combined with a preservative in an appropriate vehicle, such as, mineral oil, liquid lanolin, or white petrolatum. Sterile ophthalmic gel formulations may be prepared by suspending the active ingredient in a hydrophilic base- prepared from the combination of, for example, carbopol-940, or the like, according to the published formulations for analogous ophthalmic preparations; preservatives and tonicity agents can be incorporated.

If dosed topically, the Compounds are preferably formulated as topical ophthalmic suspensions or solutions, with a pH of about 4 to 8. The Compounds will normally be contained in these formulations in an amount .001 % to 5% by weight, but preferably in an amount of .01 % to 2% by weight. Thus, for topical presentation, 1 to 2 drops of these formulations would be delivered to the surface of the eye 1 to 4 times per day according to the discretion of a skilled clinician.

The Compounds can also be used in combination with other agents for treating glaucoma, such as, but not limited to, β-blockers (e.g., timolol, betaxolol, levobetaxolol, carteolol, levobunolol, metipranolol), carbonic anhydrase inhibitors (e.g., brinzolamide, dorzolamide, acetazolamide), αi antagonists (e.g. nipradolol), α.2 agonists (e.g., opraclonidine and brimonidine), miotics (e.g., pilocarpine) and adrenergics (epinephrine), prostaglandin analogues (e.g., latanoprost, travoprost, unoprostone, bimatoprost, and compounds set forth in U.S. Patent Nos. 5,889,052; 5,296,504; 5,422,368; 5,688,819; and 5,151 ,444, "hypotensive lipids" (e.g., compounds set forth in 5,

U.S. Patent No. 4,690,931 , particularly eliprodil and R-eliprodil, as set forth in a pending application U.S.S.N. 06/203350, and appropriate compounds from WO94/13275, such as memantine, and serotonergics (5-HT₂ agonists), such as s S-(+)-1 -(2-aminopropyl)-indazole-6-ol and other 5-HT2 agonists.

The following topical ophthalmic formulations are useful according to the present invention administered 1-4 times per day according to the discretion of a skilled clinician. 0

Vanilloid receptor-1 antagonists may be identified by at least either of the following two biological assays:

1. HEK293 cells (or other suitable cells) may be transiently transfected with VR-1 receptor cDNA followed by treatment with capsaicin to induce cell death, as 5 detailed by Caterina et al. (Nature 389:816-824 (1997)). Capsaicin antagonists are identified by their protective effect against the capsaisin-induced death in these cells.

2. VR-1 receptor antagonists may be identified using HEK293 or 132-1 N1 cells (or other suitable cells) stably expressing recombinant human VR-1 receptor, as 0 described by Gunthorpe et al. (Neuropharmacology 46:133 (2004)). Essentially, HEK293 or 132-1 N1 cells stably expressing VR-1 are cultured in 96-well plates and loaded with the Ca2+ reporter dye Fluo-3 followed by FLIPR Ca2+ imaging for compounds that antagonize capsaicin-induced increases in intracellular Ca2+.

5 The following examples are included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. However, 0 those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.

5 Cytotoxic effect of VR-1 agonist resin iferatoxin on cultured rat RGC. The cells were treated with the compound at the indicated concentration for 3 days and the surviving cells counted manually. FIG. 1 illustrates the results: asterisks represent statistical significance (p < 0.05) when compared to the vehicle control group by one-way ANOVA then Dunnett's test.

EXAMPLE 2

Cytotoxic effect of capsaicin isomers on cultured rat RGC. The cells were treated with Z-capsaicin or E-capsaicin at the indicated concentration for 3 days and the surviving cells counted manually. FIG. 2 illustrates the results: asterisks represent statistical significance (p < 0.05) when compared to the vehicle control group by one-way ANOVA then Dunnett's test.

EXAMPLE 3

Protective effect of VR-1 antagonist 6-iododihydrocapsaicin against VR-1 agonist-induced death of cultured rat RGC. The cells were treated with the compounds at the indicated concentrations for 3 days and the surviving cells counted manually. FIG. 3 illustrates the results where the VR-1 agonist is resin iferatoxin. FIG. 4 illustrates the results where the VR-1 agonist was resiniferatoxin, Z-capsaicin, or E-capsaicin: asterisks represent statistical significance (p < 0.05) when compared to the vehicle control group by one-way

ANOVA then Dunnett's test. Rftx = resiniferatoxin; Z-Cap = Z-capsaicin; E-Cap =

E-capsaicin.

Ingredients Amount (wt %)

Compound 0.01 - 2%

Hydroxypropyl methylcellulose 0.5%

Dibasic sodium phosphate 0.2% (anhydrous)

Sodium chloride 0.5%

Disodium EDTA (Edetate disodium) 0.01 %

Polysorbate 80 0.05%

Benzalkonium chloride 0.01 %

Sodium hydroxide / Hydrochloric acid For adjusting pH to 7.3 - 7.4

Purified water q.s. to 100%

EXAMPLE 5

Ingredients Amount (wt %)

Compound 0.01 - 2%

Methyl cellulose 4.0%

Dibasic sodium phosphate 0.2% (anhydrous)

Sodium chloride 0.5%

Disodium EDTA (Edetate disodium) 0.01 %

Polysorbate 80 0.05%

Benzalkonium chloride 0.01 %

Sodium hydroxide / Hydrochloric acid For adjusting pH to 7.3 - 7.4

Purified water q.s. to 100%

EXAMPLE 7

EXAMPLE 8 1OmM IV Solution w/v%

Compound 0.384%

L-Tartaric acid 2.31 %

Sodium hydroxide pH 3.8

Hydrochloric acid pH 3.8

Purified water q.s. 100%

EXAMPLE 9

5mg Capsules

Ingredient mg/capsule (Total Wt. mg)

Compound 5

Lactose, anhydrous 55.7

Starch, Sodium carboxy-methyl 8

Cellulose, microcrystalline 30

Colloidal silicon dioxide .5

Magnesium stearate .8

All of the compositions and/or methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and/or methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the invention. More specifically, it will be apparent that certain agents which are both chemically and structurally related may be substituted for the agents described herein to achieve similar results. All such substitutions and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.

All references cited herein are specifically incorporated herein by reference.

Claims

We Claim:

1. A method for treating glaucoma, said method comprising administering a composition comprising a pharmaceutically effective amount of at

5 least one vanilloid receptor-1 antagonist or a derivative thereof.

2. The method of Claim 1 wherein the vanilloid receptor-1 antagonist is selected from the group consisting of capsazepine; 6-iodono/τdihydrocapsaicin; 2- substituted pyrrolidinethiourea derivative 4a; 2-substituted pyrrol id inethiourea io derivative 4b; N-(3-acyloxy-2-benzylpropyl)-N'-[4-(methylsulfonylamino)- benzyl]thiourea derivative 1 ; N-(3-acyloxy-2-benzylpropyl)-N'-[4-

(methylsulfonylamino)-benzyl]thiourea derivative 2; N-(3-acyloxy-2-benzylpropyl)- N'-[4-(methylsulfonylamino)-benzyl]thiourea derivative 3; N-(3-acyloxy-2- benzylpropyl)-N'-[4-(methylsulfonylamino)-benzyl]thiourea derivative 12; N-(3- i5 acyloxy-2-benzylpropyl)-N'-[4-(methylsulfonylamino)-benzyl]thiourea derivative 13; N-(3-acyloxy-2-benzylpropyl)-N'-[4-(methylsulfonylamino)-benzyl]thiourea derivative 14; N-(3-acyloxy-2-benzylpropyl)-N'-[4-(methylsulfonylamino)- benzyljthiourea derivative 17; N-(3-acyloxy-2-benzylpropyl)-N'-[4-

(methylsulfonylamino)-benzyl]thiourea derivative 25; N-(3-acyloxy-2-

20 benzylpropyl)-N'-[4-(methylsulfonylamino)-benzyl]thiourea derivative 28; N-(3- acyloxy-2-benzylpropyl)-N'-[4-(methylsulfonylamino)-benzyl]thiourea derivative 33; N-(3-acyloxy-2-benzylpropyl)-N'-[4-(methylsulfonylamino)-benzyl]thiourea derivative 41 ; N-(3-acyloxy-2-benzylpropyl)-N'-[4-(methylsulfonylamino)- benzyl]thiourea derivative 42; N-(3-acyloxy-2-benzylpropyl)-N'-[4-

25 (methylsulfonylarnino)-benzyl]thiourea derivative 43; N-(3-acyloxy-2- benzylpropyl)-N'-[4-(methylsulfonylamino)-benzyl]thiourea derivative 45; N-[4- methylsulfonylamino)benzyl]thiourea derivative 2; N-[4- methylsulfonylamino)benzyl]thiourea derivative 6; N-[4- methylsulfonylamino)benzyl]thiourea derivative 7; N-[4-

30 methylsulfonylamino)benzyl]thiourea derivative 8; N-[4- methylsulfonylamino)benzyl]thiourea derivative 10; N-[4- methylsulfonylamino)benzyl]thiourea derivative 1 1 ; N-[4- methylsulfonylamino)benzyl]thiourea derivative 25; N-[4- methylsulfonylamino)benzyl]thiourea derivative 29; N-[4-

35 methylsulfonylamino)benzyl]thiourea derivative 34; N-[4- methylsulfonylamino)benzyl]thiourea derivative 46; N-[4- methylsulfonylamino)benzyl]thiourea derivative 47; N-[4- methylsulfonylamino)benzyl]thio methylsulfonylamino)benzyi]thiourea derivative 49; 7-hydroxynaphthalen-1 -yl-urea or -amide derivative 4; 7-hydroxynaphthalen-1 -yl-urea or —amide derivative 5a; 7- hydroxynaphthalen-1 -yl-urea or -amide derivative 5e; 7-hydroxynaphthalen-1-yl- urea or —amide derivative 5f; 7-hydroxynaphthalen-1 -yl-urea or -amide derivative 5h; 7-hydroxynaphthalen-1 -yl-urea or -amide derivative 5k; 7-hydroxynaphthalen- 1 -yl-urea or -amide derivative 5n; 7-hydroxynaphthalen-1 -yl-urea or -amide derivative 6k; 7-hydroxynaphthalen-1 -yl-urea or -amide derivative 6o; J- hydroxynaphthalen-1 -yl-urea or -amide derivative 6p; 7-hydroxynaphthalen-1-yl- urea or -amide derivative 6q ; N-4-substituted-benzyl-n'-tert-buty!benzyl thiourea derivative 6c; N-4-substituted-benzyl-n'-tert-butylbeπzyl thiourea derivative 6f; N- 4-substituted-benzyl-n'-tert-butylbenzyl thiourea derivative 6j; N-4-substituted- benzyl-n'-tert-butylbenzyl thiourea derivative 7b; N-4-substituted-benzyl-n'-tert- butylbenzyl thiourea derivative 7c; N-4-substituted-benzyl-n'-tert-butylbenzyl thiourea derivative 7d; N-4-substitύted-benzyl-n'-tert-butylbenzyl thiourea derivative 7e; N-4-substituted-benzyl-n'-tert-butylbenzyl thiourea derivative 7f; N- 4-substituted-benzyl-n'-tert-butylbenzyl thiourea derivative 7g; N-4-substituted- benzyl-n'-tert-butylbenzyl thiourea derivative 7j; N-4-substituted-benzyl-n'-tert- butylbenzyl thiourea derivative 7k; N-4-substituted-benzyl-n'-tert-butylbenzyl thiourea derivative 71; N-4-substituted-benzyl-n'-tert-butylbenzyl thiourea derivative 7m; N-4-substituted-benzyl-n'-tert-butyibenzyl thiourea derivative 7n; N- 4-methansulfonamidobenzyl-N'-2-substituted-4-tert-butyl-benzyl thiourea derivative 2; N-4-methansulfonamidobenzyl-N'-2-substituted-4-tert-butyl-benzyl thiourea derivative 5a; N-4-methansulfonamidobenzyl-N'-2-substituted-4-tert- butyl-benzyl thiourea derivative 5b; N-4-methansulfonamidobenzyl-N'-2- substituted-4-tert-butyl-benzyl thiourea derivative 5c; N-4- methaπsulfonamidobenzyl-N'-2-substituted-4-tert-butyl-benzyl thiourea derivative 5d; N-4-methansulfonamidobenzyl-N'-2-substituted-4-tert-butyl-benzyl thiourea derivative 5e; N-4-methansulfonamidobenzyl-N'-2-substituted-4-tert-butyl-benzyl thiourea derivative 5f; N-4-methansulfonamidobenzyl-N'-2-substituted-4-tert-butyl- benzyl thiourea derivative 5g; N-4-methansulfonamidobenzyl-N'-2-substituted-4- tert-buty) -benzyl thiourea derivative 5h; N-4-methansulfonamidobenzyl-N'-2- substituted-4-tert-butyl-benzyl thiourea derivative 5i; N-4- methansulfonamidobenzyl-N'-2-substituted-4-tert-butyl-benzyl thiourea derivative 5j; N-4-methansulfonamidobenzyl-N'-2-substituted-4-tert-butyl-benzyl thiourea derivative 5k; N-4-methansulfonamidobenzyl-N'-2-substituted-4-tert-butyl-benzyl thiourea derivative 51; N-4-methansulfonamidobenzyl-N'-2-substituted-4-tert-butyl- benzyl thiourea derivative 5m; tert-butyl-benzyl thiourea derivative 5n; N-4-methansulfonamidobenzyl-N'-2- substituted-4-tert-butyl-benzyl thiourea derivative 6d; N-4- methansulfonamidobenzyl-N'-2-substituted-4-tert-butyl-ben2yl thiourea derivative 6h; N-4-methansulfonamidobenzyl-N'-2-substituted-4-tert-butyl-benzyl thiourea derivative 6n; chain-branched 1 ,3-dibenzylthiourea derivative 6; chain-branched 1 ,3-dibenzylthiourea derivative 7; chain-branched 1 ,3-dibenzylthiourea derivative 8; chain-branched 1 ,3-dibenzylthiourea derivative 9; chain-branched 1 ,3- dibenzylthiourea derivative 10; chain-branched 1 ,3-dibenzylthiourea derivative 11 ; chain-branched 1 ,3-dibenzylthiourea derivative 17; chain-branched 1 ,3- dibenzylthiourea derivative 18; chain-branched 1 ,3-dibenzylthiourea derivative 19; chain-branched 1 ,3-dibenzylthiourea derivative 21 ; chain-branched 1 ,3- dibenzylthiourea derivative 26; chain-branched 1 ,3-dibenzylthiourea derivative 27; chain-branched 1 ,3-dibenzylthiourea derivative 28; chain-branched 1 ,3- dibenzylthiourea derivative 29; chain-branched 1 ,3-dibenzylthiourea derivative 30; chain-branched 1 ,

3-dibenzylthiourea derivative 37; N-isoquinolin-5-yl-N'-aralkyl- urea or —amide derivatives; N-(4-chlorobenzyl)-N'-(4-hydroxy-3-iodo-5- methoxybenzyl)thiourea;. 5-iodo-phenylacetylrinvanil; 6-iodo-phenylacetylrinvanil; N-aryl cinnamide derivative 1 ; N-aryl cinnamide derivative 39; N-aryl cinnamide derivative 45a; N-aryl cinnamide derivative 45b; N-aryl cinnamide derivative 45c; N-aryl cinnamide derivative 45d; N-aryl cinnamide derivative 45e; N-aryl cinnamide derivative 45f; N-aryl cinnamide derivative 46a; N-aryl cinnamide derivative 46b; N-aryl cinnamide derivative 46c; N-aryl cinnamide derivative 46d; N-aryl cinnamide derivative 46e; N-aryl cinnamide derivative 46f; N-aryl cinnamide derivative 46g; N-aryl cinnamide derivative 46h; N-aryl cinnamide derivative 46i; N-aryl cinnamide derivative 46j; N-aryl cinnamide derivative 46k; N-aryl cinnamide derivative 46I; N-aryl cinnamide derivative 46m; N-aryl cinnamide derivative 46n; N-aryl cinnamide derivative 46o; N-aryl cinnamide derivative 46p; N-aryl cinnamide derivative 47a; N-aryl cinnamide derivative 47b; N-aryl cinnamide derivative 47d; N-aryl cinnamide derivative 48b; N-aryl cinnamide derivative 48c; N-aryl cinnamide derivative 48d; N-aryl cinnamide derivative 48e; N-aryl cinnamide derivative 48f; N-aryl cinnamide derivative 48h; N-aryl cinnamide derivative 48i; N-aryl cinnamide derivative 48j; N-aryl cinnamide derivative 48k; N- aryl cinnamide derivative 48I; N-aryl cinnamide derivative 48m; N-aryl cinnamide derivative 48n; N-aryl cinnamide derivative 48p; N-aryl cinnamide derivative 48q; N-aryl cinnamide derivative 48s; N-aryl cinnamide derivative 48t; N-aryl cinnamide derivative 48u; N-aryl cinnamide derivative 48v; N-aryl cinnamide derivative 48w; N-aryl cinnamide derivative cinnamide derivative 49b, N, N', N"-trisubstituted thiourea derivative 8k; N, N', N"- trisubstituted thiourea derivative 81; N, N', N"-trisubstituted thiourea derivative 8n;

N, N', N"-trisubstituted thiourea derivative 8x; N₁ N', N"-trisubstituted thiourea derivative 8y; N, N', N"-trisubstituted thiourea derivative 8z; N, N', N"-trisubstituted thiourea derivative 8a'; 4-(2-pyridyl)piperazine-1 -carboxamide derivative 1 ; 4-(2- pyridyl)piperazine-1 -carboxamide derivative 2; 4-(2-pyridyl)piperazine-1- carboxamide derivative 3; 4-(2-pyridyl)piperazine-1 -carboxamide derivative 5; A-

(2-pyridyl)piperazine-1-carboxamide derivative 6; 4-(2-pyridyl)piperazine-1- carboxamide derivative 7; 4-(2-pyridyl)piperazine-1-carboxamide derivative 8; A-

(2-pyridyl)piperazine-1-carboxamide derivative 10; 4-(2-pyridyl)piperazine-1- carboxamide derivative 11 ; 4-(2-pyridyl)piperazine-1 -carboxamide derivative -12;

4-(2-pyridyl)piperazine-1 -carboxamide derivative 13; 4-(2-pyridyl)piperazine-1- carboxamide derivative 14; 4-(2-pyridyl)piperazine-1 -carboxamide derivative 15; 4-(2-pyridyl)piperazine-1 -carboxamide derivative 16; 4-(2~pyridyl)piperazine-1- carboxamide derivative 18; 4-(2-pyridyl)piperazine-1-carboxamide derivative 19;

4-(2-pyridyl)piperazine-1 -carboxamide derivative 20; 4-(2-pyridy!)piperazine-1- carboxamide derivative 21 ; 4-(2-pyridyl)piperazine-1 -carboxamide derivative 22;

4-(2-pyridyl)piperazine-1 -carboxamide derivative 23; 4-(2-pyridyl)piperazine~1- carboxamide derivative 24; 4-(2-pyridyl)piperazine-1 -carboxamide derivative 25;

4-(2-pyridyl)piperazine-1 -carboxamide derivative 28; 4-(2-pyridyl)piperazine-1- carboxamide derivative 30; 4-(2-pyridyl)piperazine-1 -carboxamide derivative 31 ;

19N-[4-methylsulfonyiamino)benzyl] thiourea derivative 2; 19N-[4- methylsulfonylamino)benzyl] thiourea derivative 6; 19N-[4- methylsuifonylamino)benzyl] thiourea derivative 7; 19N-[4- methylsulfonylamino)benzyl] thiourea derivative 8; 19N-[4- methylsulfonylamino)benzyl] thiourea derivative 10; 19N-[4- methylsulfonylamino)benzyl] thiourea derivative 1 1 ; 19N-[4- methylsulfonylamino)benzyl] thiourea derivative 25; 19N-[4- methylsulfonylamiπo)benzyl] thiourea derivative 29; 19N-[4- methylsulfonylamino)benzyl] thiourea derivative 34; 19N-[4- methylsulfonylamino)benzyl] thiourea derivative 46; 19N-[4- methylsulfony!amino)benzyi] thiourea derivative 47; 19N-[4- methylsulfonylamino)benzyl] thiourea derivative 48; 19N-[4- methylsulfonylamino)benzyl] thiourea derivative 49; 7-hydroxynaphthalen-1-yl- urea derivative 4; 7-hydroxynaphthalen-1-yl-urea derivative 5a; 7- hydroxynaphthaien-1-yl-urea derivative 5e; 7-hydroxynaphthalen-1-yl-urea derivative 5f; 7-hydroxynaphth?

1 -yl-urea derivative 5k; 7-hydroxynaphthalen-1-yl-urea derivative 5n; 7- hydroxynaphthalen-1-yl-urea derivative 6k; 7-hydroxynaphthalen-1-yl-urea derivative 6o; 7-hydroxynaphthalet>1-yl-urea derivative 6p; 7-hydroxynaphthalen- 1 -yl-urea derivative 6q; 7-hydroxynaphthalen-1 -yl-amide derivative 4; 7- hydroxynaphthalen-1-yl-amide derivative 5a; 7-hydroxynaphthalen-1 -yl-amide derivative 5e; 7-hydroxynaphthalen-1 -yl-amide derivative 5f; 7- hydroxynaphthalen-1 -yl-amide derivative 5h; 7-hydroxynaphthalen-1 -yl-amide derivative 5k; 7-hydroxynaphthalen-1 -yl-amide derivative 5n; 7- hydroxynaphthalen-1 -yl-amide derivative 6k; 7-hydroxynaphthalen-1 -yl-amide derivative 6o; 7-hydroxynaphthalen-1 -yl-amide derivative 6p; 7- hydroxynaphthalen-1 -yl-amide derivative 6q; N-4-substituted-benzyl-n'-tert- butylbenzyl thiourea derivative 6c; N-4-substituted-benzyl-n'-tert-butylbenzyl thiourea derivative 6f; N-4-substituted-benzyl-n'-tert-butylbenzyl thiourea derivative 6j; N-4-substituted-benzyl-n'-tert-butylbenzyl thiourea derivative 7b; N- 4-substituted-benzyl-n'-tert-butylbenzyl thiourea derivative 7c; N-4-substituted- benzyl-n'-tert-butylbenzyl thiourea derivative 7d; N-4-substituted-benzyl-n'-tert~ butylbenzyl thiourea derivative 7e; N-4-substituted-benzyl-n'-tert-butylbenzyl thiourea derivative 7f; N-4-substituted-benzyl-n'-tert-butylbenzyl thiourea derivative 7g; N-4-substituted-benzyl-n'-tert-butylbenzyl thiourea derivative 7j; N- 4-substituted-benzyl-n'-tert-butylbenzyl thiourea derivative 7k; N-4-substituted- benzyl-n'-tert-butylbenzyl thiourea derivative 7I; N-4-substituted-benzyl-n'-tert- butylbenzyl thiourea derivative 7m; N-4-substituted-benzyl-n'-tert*utylbenzyl thiourea derivative 7n; N-4-methansulfonamidobenzyl-N'-2-substituted-4-tert- butyl-benzyl thiourea derivative 2; N-4-methansulfonamidobenzyl-N'-2-substituted- 4-tert-butyl-benzyl thiourea derivative 5a; N-4-methansulfonamidobenzyl-N'-2- substituted-4-tert-butyl-benzyl thiourea derivative 5b; N-4- methansulfonamidobenzyl-N'-2-substituted-4-tert-butyl-benzyl thiourea derivative 5c; N-4-methansulfonamidobenzyl-N'-2-substituted-4-tert-butyl-benzyl thiourea derivative 5d; N-4-methansulfonamidobenzyl-N'-2-substituted-4-tert-butyl-benzyl thiourea derivative 5e; N-4-methansulfonamidobenzyl-N'-2-substituted-4-tert- butyl-benzyl thiourea derivative 5f; N-4-methansulfonamidobenzyl-N'-2- substituted-4-tert-butyl-benzyl thiourea derivative 5g; N-4- methansulfonamidobenzyl-N'-2-substituted-4-tert-butyl-benzyl thiourea derivative 5h; N-4-methansulfonamidobenzyl-N'-2-substituted-4-tert-butyl-benzyl thiourea derivative 5i; N-4-methansulfonamidobenzyl-N'-2-substituted-4-tert-butyl-benzyl thiourea derivative 5j; N-4-methansulfonamidobenzyl-N'-2-substituted-4-tert-butyl- benzyl thiourea derivative 5k; tert-butyl-benzyl thiourea derivative 51; N-4-methansulfonamidobenzyl-N'-2- substituted-4-tert-butyl-benzyl thiourea derivative 5m; N-4- methansulfonamidobenzyl-N'-2-substituted-4-tert-butyl-benzyl thiourea derivative s 5n; N-4-methansulfonamidobenzyl-N'-2-substituted-4-tert-butyl-benzyl thiourea derivative 6d; N-4-methansulfonamidobenzyl-N'-2-substituted-4-tert-butyl-benzyl thiourea derivative 6d; and N-4-methansulfonamidobenzyl-N'-2-substituted-4-tert- butyl-benzyl thiourea derivative 6n.

o 3. The method of claim 1 , wherein the preferred compound is (4-(3- trifluoromethylpyridin-2-yl)piperazine-1 -carboxylic acid (5-trifluoromethylpyridin-2- yl)amide (Compound 41 disclosed in Swanson et al., J. Med. Chem., 48: 1857- 1872 (2005)).

s 4. The method of claim 1 , wherein the composition is delivered via a method selected from the group consisting of oral administration, intravitreal injection, topical ocular, transdermal patch, subdermal, parenteral, intraocular, subconjunctival, retrobulbar injection, subtenoπ's injection, trans scleral (including iontophoresis), slow release biodegradable polymers, and liposomes. 0

5. The method of claim 4, wherein the composition is delivered via oral administration.

6. A method for protecting retinal cells from damage and/or apoptosis 5 resulting from glaucoma, said method comprising administering to a patient a composition comprising a pharmaceutically effective ^mount of at least one vanilloid receptor-1 antagonist or a derivative thereof.

7. The method of Claim 6 wherein the vanilloid receptor-1 antagonist is 0 selected from the group consisting of capsazepine; 6-iodono/idihydrocapsaicin; 2- substituted pyrrolidinethiourea derivative 4a; 2-substituted pyrrolidinethiourea derivative 4b; N-(3-acyloxy-2-benzylpropyl)-N'-[4-(methylsulfonylamino)- benzyl]thiourea derivative 1 ; N-(3-acyloxy-2-benzylpropyl)-N'-[4-

(methylsulfonylamino)-benzyl]thiourea derivative 2; N-(3-acyloxy-2-benzylpropyl)- 5 N'-[4-(methylsuIfonylamino)-benzyl]thiourea derivative 3; N-(3-acyloxy-2- benzylpropyl)-N'-[4-(methylsulfonylamino)-benzyl]thiourea derivative 12; N-(3- acyloxy-2-benzylpropyl)-N'-[4-(methylsulfonylamino)-benzyl]thiourea derivative 13; N-(3-acyloxy-2-benzylpropyl)-N' derivative 14; N-(3-acyloxy-2-benzylpropyl)-N'-[4-(methylsulfonylamino)- benzyl]thiourea derivative 17; N-(3-acyloxy-2-benzylpropyl)-N'-[4-

(methylsulfonylamino)-benzyl]thiourea _. derivative 25; N-(3-acyloxy-2-

5 benzylpropyl)-N'-[4-(methylsulfonylamino)-benzyl]thiourea derivative 28; N-(3- acyloxy-2-benzylpropyl)-N'-[4-(methylsulfonylamino)-benzyl]thiourea derivative 33; N-(3-acyloxy-2-benzylpropyl)-N'-[4-(methylsulfonylamino)-benzyl]thiourea derivative 41 ; N-(3-acyloxy-2-benzylpropyl)-N'-[4-(methylsulfonylamino)- beπzyl]thiourea derivative 42; N-(3-acyloxy-2-benzylpropyl)-N'-[4- io (methylsulfonylamino)-benzyl]thiourea derivative 43; N-(3-acyloxy-2- benzylpropyl)-N'-[4-(methylsulfonylamino)-benzyl]thiourea derivative 45; N-[4- methylsulfonylamino)benzyl]thiourea derivative 2; N-[4- methylsulfonylamino)benzyl]thiourea derivative 6; N-[4- methylsulfonyiamino)benzyl]thiourea derivative 7; N-[4- i5 methylsulfonylamino)benzyl]thiourea derivative 8; N-[4- methylsulfonylamino)benzyl]thiourea derivative 10; N-[4- methylsulfonylamino)benzyl]thiourea derivative 11 ; N-[4- methyisulfonylamino)benzyl]thiourea derivative 25; N-[4- methylsulfonylamino)benzyl]thiourea derivative 29; N-[4-

₂o methylsulfonylamino)benzyl]thiourea derivative 34; N-[4- methylsulfonylamino)benzyl]thiourea derivative 46; N-[4- methylsulfonylamino)benzyl]thiourea derivative 47; N-[4- methylsulfonylamino)benzyl]thiourea derivative 48; N-[4- methylsulfonylamino)benzyl]thiourea derivative 49; 7-hydroxynaphthalen-1-yl-urea

25 or —amide derivative 4; 7-hydroxynaphthalen-1-yl-urea or -amide derivative 5a; 7- hydroxynaphthalen-1-yl-urea or -amide derivative 5e; 7-hydroxynaphthalen-1-yl- urea or —amide derivative 5f; 7-hydroxynaphthalen-1-yl-urea or —amide derivative 5h; 7-hydroxynaphthalen-1-yl-urea or — amide derivative 5k; 7-hydroxynaphthalen- 1-yl-urea or —amide derivative 5n; 7-hydroxyπaphthalen-1-yl-urea or —amide

30 derivative 6k; 7-hydroxynaphthalen-1-yl-urea or —amide derivative 6o; 7- hydroxynaphthalen-1-yl-urea or -amide derivative 6p; 7-hydroxynaphthalen-1-yl- urea or -amide derivative 6q ; N-4-substituted-benzyl-n'-tert-butylbenzyl thiourea derivative 6c; N-4-substituted-benzyl-n'-tert-butylbenzyl thiourea derivative 6f; N- 4-substituted-benzyl-n'-tert-butylbenzyl thiourea derivative 6j; N-4-substituted-

35 benzyl-n'-tert-butylbenzyl thiourea derivative 7b; N-4-substituted-benzyl-n'-tert- butylbenzyl thiourea derivative 7c; N-4-substituted-benzyl-n'-tert-butylbenzyl thiourea derivative 7d; N-4-substituted-benzyl-n'-tert-butylbenzyl thiourea derivative 7e; N-4-substituted-t

4-substituted-benzyl-n'-tert-butylbenzyl thiourea derivative 7g; N-4-substituted- benzyl-n'-tert-butylbenzyl thiourea derivative 7j; N-4-substituted-benzyl-n'-tert- butylbenzyl thiourea derivative 7k; N-4-substituted-benzyl-n'-tert-butylbenzyl thiourea derivative 71; N-4-substituted-benzyl-n'-tert-butylbenzyl thiourea derivative 7m; N-4-substituted-benzyl-n'-tert-butylbenzyl thiourea derivative 7n; N- 4-methansulfonamidobenzyl-N'-2-substituted-4-tert-butyi-benzyl thiourea derivative 2; N-4-methansulfonamidobenzyl-N'-2-substituted-4-tert-butyl-benzyl thiourea derivative 5a; N-4-methansulfonamidobenzyl-N'-2-substituted-4-tert- butyl-benzyl thiourea derivative 5b; N-4-methansulfonamidobenzyl-N'-2- substituted-4-tert-butyl-benzyl thiourea derivative 5c; N-4- methansulfonamidobenzyl-N'-2-substituted-4-tert-butyl-benzyl thiourea derivative 5d; N-4-methansulfonamidobenzyl-N'-2-substituted-4-tert-butyl-benzyl thiourea derivative 5e; N-4-methansulfonamidobenzyl-N'-2-substituted-4-tert-butyl-benzyl thiourea derivative 5f; N-4-methansulfonamidobenzyl-N'-2-substituted-4-tert-butyl- benzyl thiourea derivative 5g; N-4-methansulfonamidobenzyl-N'-2-substituted-4- tert-butyl -benzyl thiourea derivative 5h; N-4-methansulfonamidobenzyl-N'-2- substituted-4-tert-butyl-benzyl thiourea derivative 5i; N-4- methansulfonamidobenzyl-N'-2-substituted-4-tert-butyl-benzyl thiourea derivative 5j; N-4-methansulfonamidobenzyl-N'-2-substituted-4-tert-butyl-benzyl thiourea derivative 5k; N-4-methansulfonamidobenzyl-N'-2-substituted-4-tert-butyI-benzyl thiourea derivative 51; N-4-methansulfonamidobenzyl-N'-2-substituted-4-tert-butyl- benzyl thiourea derivative 5m; N-4-methansulfonamidobenzyl-N'-2-substituted-4- tert-butyl-benzyl thiourea derivative 5n; N-4-methansulfonarnidobenzyl-N'-2- substituted-4-tert-butyl-benzyl thiourea derivative 6d; N-4- methansulfonamidobenzyl-N'-2-substituted-4-tert-butyl-benzyl thiourea derivative 6h; N-4-methansulfonamidobenzyl-N'-2-substituted-4-tert-butyl-benzyl thiourea derivative 6n; chain-branched 1 ,3-dibenzylthiourea derivative 6; chain-branched 1 ,3-dibenzylthiourea derivative 7; chain-branched 1 ,3-dibenzylthiourea derivative 8; chain-branched 1 ,3-dibenzylthiourea derivative 9; chain-branched 1 ,3- dibenzylthiourea derivative 10; chain-branched 1 ,3-dibenzylthiourea derivative 11 ; chain-branched 1 ,3-dibenzylthiourea derivative 17; chain-branched 1 ,3- dibenzylthiourea derivative 18; chain-branched 1 ,3-dibenzylthiourea derivative 19; chain-branched 1 ,3-dibenzylthiourea derivative 21 ; chain-branched 1 ,3- dibenzylthiourea derivative 26; chain-branched 1 ,3-dibenzylthiourea derivative 27; chain-branched 1 ,3-dibenzylthiourea derivative 28; chain-branched 1,3- dibenzylthiourea derivative 29; chain-branched 1 ,3-dibenzylthiourea derivative 30; chain-branched 1 ,3-dibenzylthic urea or -amide derivatives; N-(4-chlorobenzyl)-N'-(4-hydroxy-3-iodo-5- methoxybenzyl)thiourea; 5-iodo-phenylacetylrinvanil; 6-iodo-phenylacetylrinvanil; N-aryl cinnamide derivative 1 ; N-aryl cinnamide derivative 39; N-aryl cinnamide derivative 45a; N-aryl cinnamide derivative 45b; N-aryl cinnamide derivative 45c; N-aryl cinnamide derivative 45d; N-aryl cinnamide derivative 45e; N-aryl cinnamide derivative 45f; N-aryl cinnamide derivative 46a; N-aryl cinnamide derivative 46b; N-aryl cinnamide derivative 46c; N-aryl cinnamide derivative 46d; N-aryl cinnamide derivative 46e; N-aryl cinnamide derivative 46f; N-aryl cinnamide derivative 46g; N-aryl cinnamide derivative 46h; N-aryl cinnamide derivative 46i; N-aryl cinnamide derivative 46j; N-aryl cinnamide derivative 46k; N-aryl cinnamide derivative 461; N-aryl cinnamide derivative 46m; N-aryl cinnamide derivative 46n; N-aryl cinnamide derivative 46o; N-aryl cinnamide derivative 46p; N-aryl cinnamide derivative 47a; N-aryl cinnamide derivative 47b; N-aryl cinnamide derivative 47d; N-aryl cinnamide derivative 48b; N-aryl cinnamide derivative 48c; N-aryl cinnamide derivative 48d; N-aryl cinnamide derivative 48e; N-aryl cinnamide derivative 48f; N-aryl cinnamide derivative 48h; N-aryl cinnamide derivative 48i; N-aryl cinnamide derivative 48j; N-aryl cinnamide derivative 48k; N- aryl cinnamide derivative 481; N-aryl cinnamide derivative 48m; N-aryl cinnamide derivative 48n; N-aryl cinnamide derivative 48p; N-aryl cinnamide derivative 48q; N-aryl cinnamide derivative 48s; N-aryl cinnamide derivative 48t; N-aryl cinnamide derivative 48u; N-aryl cinnamide derivative 48v; N-aryl cinnamide derivative 48w; N-aryl cinnamide derivative 48x; N-aryl cinnamide derivative 49a; N-aryl cinnamide derivative 49b; N, N', N"-trisubstituted thiourea derivative 8k; N₁ N^f, N"- trisubstituted thiourea derivative 81; N, N', N"-trisubstituted thiourea derivative 8n; N, N', N"-trisubstituted thiourea derivative 8x; N, N', ^T-trisubstituted thiourea derivative 8y; N, N', N"-trisubstituted thiourea derivative 8z; N, N', N"-trisubstituted thiourea derivative 8a'; 4-(2-pyridyl)piperazine-1 -carboxamide derivative 1 ; 4-(2- pyridyl)piperazine-1-carboxamide derivative 2; 4-(2-pyridyl)piperazine-1- carboxamide derivative 3; 4-(2-pyridyl)piperazine-1-carboxamide derivative 5; A- (2-pyridyl)piperazine-1 -carboxarnide derivative 6; 4-(2-pyridyl)piperazine-1- carboxamide derivative 7; 4-(2-pyridyl)piperazine-1 -carboxamide derivative 8; A- (2-pyridyl)piperazine-1 -carboxamide derivative 10; 4-(2-pyridyl)piperazine-1~ carboxamide derivative 11 ; 4-(2-pyridyl)piperazine-1-carboxamide derivative -12; 4-(2-pyridyl)piperazine-1 -carboxamide derivative 13; 4-(2-pyridyl)piperazine-1- carboxamide derivative 14; 4-(2-pyridyl)piperazine-1-carboxamide derivative 15; 4-(2-pyridyl)piperazine-1 -carboxamide derivative 16; 4-(2-pyridyl)piperazine-1- carboxamide derivative 18; 4-(

4-(2-pyridyl)piperazine-1-carboxamide derivative 20; 4-(2-pyridyl)piperazine-1- carboxamide derivative 21 ; 4-(2-pyridyl)piperazine-1 -carboxamide derivative 22; 4-(2-pyridyl)piperazine-1 -carboxamide derivative 23; 4-(2-pyridyl)piperazine-1- carboxamide derivative 24; 4-(2-pyridyl)piperazine-1 -carboxamide derivative 25; 4-(2-pyridyl)piperazine-1 -carboxamide derivative 28; 4-(2-pyridyl)piperazine-1- carboxamide derivative 30; 4-(2-pyridyl)piperazine-1-carboxamide derivative 31 ; 19N-[4-methylsulfonylamino)benzyl] thiourea derivative 2; 19N-[4- methyisulfonylamiπo)beπzyl] thiourea derivative 6; 19N-[4- methylsulfonylarnino)benzyl] thiourea derivative 7; 19N-[4- methylsulfonylamino)benzyl] thiourea derivative 8; 19N-[4- methylsulfonylamino)benzyl] thiourea derivative 10; 19N-[4- methylsulfonylamino)benzyl] thiourea derivative 1 1 ; 19N-[4- methylsulfonylamino)benzyl] thiourea derivative 25; 19N-[4- methylsulfonylamino)benzyl] thiourea derivative 29; 19N-[4- methylsulfonylamino)benzyl] thiourea derivative 34; 19N-[4- methylsulfonylamino)benzyl] thiourea derivative 46; 19N-[4- methylsulfonylamino)benzyl] thiourea derivative 47; 19N-[4- methylsulfonylamino)benzyl] thiourea derivative 48; 19N-[4- methylsulfonylamino)benzyl] thiourea derivative 49; 7-hydroxynaphthalen-1-yl- urea derivative 4; 7-hydroxynaphthalen-1-yl-urea derivative 5a; 7- hydroxynaphthalen-1-yl-urea derivative 5e; 7-hydroxynaphthalen-1-yl-urea derivative 5f; 7-hydroxynaphthalen-1-yl-urea derivative 5h; 7-hydroxynaphthalen- 1 -yl-urea derivative 5k; 7-hydroxynaphthalen-1-yl-urea derivative 5n; 7- hydroxynaphthalen-1-yl-urea derivative 6k; 7-hydroxynaphthalen-1-yl-urea derivative 6o; 7-hydroxynaphthalen-1 -yl-urea derivative 6p; 7-hydroxynf.phthalen- 1 -yl-urea derivative 6q; 7-hydroxynaphthalen-1-yl-amide derivative 4; 7- hydroxynaphthalen-1-yl-amide derivative 5a; 7-hydroxynaphthalen-1-yl-amide derivative 5e; 7-hydroxynaphthalen-1-yl-amide derivative 5f; 7- hydroxynaphthalen-1-yl-amide derivative 5h; 7-hydroxynaphthalen-1-yl-amide derivative 5k; 7-hydroxynaphthalen-1-yl-amide derivative 5n; 7- hydroxynaphthalen-1-yl-amide derivative 6k; 7-hydroxynaphthalen-1-yl-amide derivative 6o; 7-hydroxynaphthalen-1-yl-amide derivative 6p; 7- hydroxynaphthalen-1-yl-amide derivative 6q; N-4-substituted-benzyl-n'-tert- butylbenzyl thiourea derivative 6c; N-4-substituted-benzyl-n'-tert-butylbenzyl thiourea derivative 6f; N-4-substituted-benzyl-n'-tert-butylbenzyl thiourea derivative 6j; N-4-substituted-benzyl-n'-tert-butylbenzyl thiourea derivative 7b; N- 4-substituted-benzyl-rr-tert-butyl benzyl-n'-tert-butylbenzyl thiourea derivative 7d; N-4-substituted-benzyl-n'-tert- butylbenzyl thiourea derivative 7e; N-4-substituted-benzyl-n'-tert-butylbenzyl thiourea derivative 7f; N-4-substituted-benzyl-n'-tert-butylbenzyl thiourea

5 derivative 7g; N-4-substituted-benzyl-n'-tert-butylbenzyl thiourea derivative 7j; N- 4-substituted-benzyl-n'-tert-butylbenzyl thiourea derivative 7k; N-4-substituted- benzyl-n'-tert-butylbenzyl thiourea derivative 71; N-4-substituted-benzyl-n'-tert- butylbenzyl thiourea derivative 7m; N-4-substituted-benzyl-n'-tert-butylbenzyl thiourea derivative 7n; N-4-methansulfonamidόbenzyl-N"-2-substituted-4-tert- io butyl-benzyl thiourea derivative 2; N-4-methansulfonamidobenzyl-N'-2-substituted- 4-tert-butyl-benzyl thiourea derivative 5a; N-4-methansulfonamidobenzyl-N'-2- substituted-4-tert-butyl-benzyl thiourea derivative 5b; N-4- methansulfonamidobenzyl-N'-2-substituted-4-tert-butyl-benzyl thiourea derivative 5c; N-4-methansulfonamidobenzyl-N'-2-substituted-4-tert-butyl-benzyl thiourea i5 derivative 5d; N-4-methansulfonamidobenzyl-N'-2-substituted-4-tert-butyl-benzyl thiourea derivative 5e; N-4-methansulfonamidobenzyl-N'-2-substituted-4-tert- butyl-benzyl thiourea derivative 5f; N-4-methansulfonamidobenzyl-N'-2- substituted-4-tert-butyl-benzyl thiourea derivative 5g; N-4- methansulfonamidobenzyl-N'-2-substituted-4-tert-butyl-benzyl thiourea derivative

20 5h; N-4-methansulfonamidobenzyl-N'-2-substituted-4-tert-butyl-benzyl thiourea derivative 5i; N-4-methansulfonamidobenzyl-N'-2-substituted-4-tert-butyl-benzyl thiourea derivative 5j; N-4-methansulfonamidobenzyl-N'-2-substituted-4-tert-butyl- benzyl thiourea derivative 5k; N-4-methansulfonamidobenzyi-N'-2-substituted-4- tert-butyl-benzyl thiourea derivative 51; N-4-methansulfonamidobenzyl-N'-2-

25 substituted-4-tert-butyl-benzyl thiourea derivative 5m; N-4- methansulfonamidobenzyl-N'-2-substituted-4-tert-butyl-benzyl thiourea derivative 5n; N-4-methansulfonamidobenzyl-N'-2-substituted-4-tert-butyl-benzyl thiourea derivative 6d; N-4-methansulfonamidobenzyl-N'-2-substituted-4-tert-butyl-benzyl thiourea derivative 6d; and N-4-methansulfonamidobenzyl-N^J-2-substituted-4-tert-

30 butyl-benzyl thiourea derivative 6n..

8. The method of claim 6, wherein the preferred compound is (4-(3- trifluoromethylpyridin-2-yl)piperazine-1 -carboxylic acid (5-trifluoromethylpyridin-2- yl)amide (Compound 41 disclosed in Swanson et al., J. Med. Chem., 48: 1857- 35 1872 (2005)).

9. The method of clair method selected from the group consisting of oral administration, intravitreal injection, topical ocular, transdermal patch, subdermal, parenteral, intraocular, subconjunctival, retrobulbar injection, subtenon's injection, trans scleral (including iontophoresis), slow release biodegradable polymers, and liposomes.

10. The method of claim 9, wherein the composition is delivered via oral administration.